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L0301P23 - Cell Cycle: Proliferation, Maturation and Apoptosis
Proliferation Growth *cells produced so that multicellular organisms can grow Replacement *any cells in multicellular organisms that have been worn out or have been damage and need to be replaced by cellular division Cell Cycle *'Goal:' to produce two genetically identical cells from on precursor cell *each daughter cell should have an entire copy of the genome and be immediately functional *division is initiated through the integration of external signals and the cell’s internal clock Orderly sequence: #The cell duplicates its contents #*replication of DNA and accurate separation of chromosomes #*doubling of cell mass #The cell physically divides in two #*each daughter cell receives a copy of the entire genome #*each cell receives half the cell contents (so that cells do not reduce their size upon division) Details vary from organism to organism *bacteria - as little as 20 minutes *yeast - 90-120 minutes *mammalian cells - from 24 hours upwards Interphase *includes G1, DNA replication and G2 phase *several checkpoints that are critical and determine whether cells continue through the cycle, or enter apoptosis Gap 0 (G0) Stage *non-dividing cells that do not leave G1 *e..g. nerve cells Gap 1 (G1) Phase *longest period of the cell cycle **but may only be a few minutes in some rapidly dividing embryonic cells *cell functions normally during growth *protein and organelle synthesis such that the cell doubles in size *prepares the cell to undergo the next stage Regulatory Molecules *cyclin *cyclin-dependent kinases (CDKs) G1/S Transition #Cyclin D produced and binds to CDK4 #After a complex pathway, activates Cyclin E #Binds to CDK2 o form Cyclin E-CDK2 complexes #Cyclin E-CDK2 actives and prepares cell for S phase #*levels of the transcription factors that promote the expression of the S-phase cyclins and DNA synthesis enzymes are increased #*levels of the molecules involved in inhibition of entry into S phase are decreased (controlled degradation) Synthesis (S) Phase *DNA is replicated to produce two identical copies of each chromosome *replication begins at many sites along the length of a chromosome from pre-replication complexes *new histone proteins are synthesised for the new DNA to form new chromosomes Checkpoint *checks for any incorrect copying which may result in mutations that stop the new cell working S-Phase Control *active S cyclin-CDK complexes phosphorylate proteins in the pre-replication complexes on DNA replication origins *ensures that **each pre-replication complex is activated to initiate chromosomal replication **new complexes are prevented from forming, i.e. genome is copied only once Gap 2 Phase *prepares itself for mitosis by synthesising components to ensure the survival and functionality of each daughter cell Mitosis Phase *mitotic cyclin-CDK complexes are activated and promote: **stimulation of proteins involved in chromatin condensation **mitotic spindle formation **degradation of chromosomal structural proteins **procession through the stages of mitosis Interphase (pre-division) *chromosomes are decondensed, and in an active transcriptional state *cells are now 4n due to replication Prophase *early **chromatin condenses to join at centromere and forms chromosomes *late **nuclear envelope and nucleoli disappears **spindle apparatus forms in the cytoplasm Metaphase *spindles grow and attaches to centromere *chromosomes move to equatorial plate **metaphase plate - formed along the midline of the cell between the poles *chromosomes are now at their most condensed state *best phase for diagnostics - karyotypes Anaphase *centromeres divide to create two chromosomes **i.e. sister chromatids are separated *spindle fibres shorten and sister chromosomes drawn to opposite poles *poles of the spindle apparatus are pushed apart as the cell elongates *results in the exact distribution of one complete diploid complement of gene;c information to each daughter cell Telophase *reassembly of nuclear envelope to surround each set of daughter chromosomes *the nucleoli reappear inside the newly formed nuclei *furrow appears around the cell that eventually pinches the cell into two new cells *chromosomes decondenses in the daughter cells to become chromatin and the cells are once again in Interphase Cytokinesis *cells cytoplasms separate completely *parent cell has fully divided into 2 daughter cells with identical genetic information Cycle Checkpoints Two important proteins which act to stop the cell from dividing when it is not required: Rb (retinoblastoma protein) *if inactivated by phosphorylation, genes can be transcribed to allow the cell to enter the S phase *mutations results in retinoblastoma (eye cancer) P53 *activates transcription of inhibitors of CDK *works to block transition from G1 to S *more than 50% of human tumours have a mutation/deletion of the p53 gene If either are inactivated/not functional, they cannot stop the cell cycle Maturation *humans develop from a single fertilised oocyte which is totipotent *development by growth and differentiation *multicellular organisms **groups of cells (same type) form tissues **multiple tissues form an organ **cells that become a part of a tissue or organ (specialised): ***lose their ability survive without support of other cells ***become dependent on other cells to work as a group to govern as a whole differentiation —> maturation —> specialisation Differentiation *different groups of genes expressed so the cell becomes specialised for a particular function Specialisation *specific groups of genes are switched on/off to generate and maintain specific cells types *if not properly regulated - vital problems in cell growth can lead to diseases like cancer Master Regulator Example GATA1 *DNA sequence-specific zinc finger transcription factor *essential for differentiation for various cell types in the blood system *if absent, precursor cells do not mature and instead undergo apoptosis **no normal blood system development Reproduction *maturation is accompanied by the expression of specific groups of genes that support the changes they are undergoing, and their final functional state *E.g.: specific genes switched on/off to allow embryo development **Blimp1: specification of the germ line lineage Apoptosis *programmed cell death in response to damage or disease *balance maintains the appropriate number of cells in the tissues *originally discovered in C.elegans (roundworm) *activated by caspases when the cell: **receives no signals at all **receives external signal to die ***toxins, hormones, gases **receives intracellular signal ***DNA damage, mitochondria problems Process #cell shrinks and becomes rounder through breakdown of the cytoskeleton by caspases #cytoplasm appears dense and organelles tightly packed #pyknosis - chromatin undergoes condensation into compact patches against the nuclear envelope #karyorrhexis - nuclear envelope becomes discontinuous and DNA is fragmented #blebs (irregular membrane buds) formed #cell break apart into several vesicles called apoptotic bodies #apoptotic bodies are phagocytosed by macrophages Example:  Formation of a hollow tube *cells undergo apoptosis to form the lumen *multiple lumen form then coalesce to generate a continuous lumen *produces glands and pancreas Necrosis *death of cells caused by factors external to the cell or tissue **injury, cancer, infarction, poisons and inflammation *cells swell or burst and relating their intracellular contents *necrotic tissue needs to be removed surgically *necrosing cells lack chemical signals **phagocytes do not locate them and cannot engulf the dead cells **leads to a buildup of dead tissue and cell debris Comparison of Apoptosis and Necrosis *necrosis is induced by tissue injury **cells swell and burst releasing their intracellular contents **can lead to damage of surrounding cells causing inflammation *apoptosis is programmed cell death **this is a regulated process in which cells undergo well-defined morphological changes *while apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal